Process for preparing 1, 3, 4, 5-tetrahydro-5-phenyl-2h-1, 4-benzodiazepin-2-ones



United States Patent O 3,414,562 PROCESS FOR PREPARINGl,3,4,5-TETRAHYDRO-5- PHENYL-ZH-1,4-BENZODIAZEPIN-2-ONES Giles AllanArcher, Essex Fells, and Leo Henryk Sternbach, Upper Montclair, N.J.,assignors to Holfmann-La Roche Inc., Nutley, N.J., a corporation of NewJersey No Drawing. Original application June 15, 1964, Ser. No. 375,292,now Patent No. 3,370,091, dated Feb. 20, 1968. Divided and thisapplication Apr. 21, 1967, Ser. No.

8 Claims. (Cl. 260--239.3)

ABSTRACT OF THE DISCLOSURE A process for preparing1,3,4,5-tetrahydro-5-phenyl- 2H-1,4-benzodiazepin-2-ones which are aknown pharmaceutically useful class of compounds.

CROSS REFERENCES TO RELATED APPLICATIONS This application is adivisional application of Ser. No. 375,292, Archer et al., filed June15, 1964, now US. Patent 3,370,091 issued Feb. 20, 1968.

BACKGROUND OF INVENTION The only methods described in the prior art forthe formation of 1,3,4,S-tetrahydro5-phenyl-2H-1,4- benzodiazepin-Z-onesinvolve the preparation of other 1,4-benzodiazepines followed byconversion to the desired 1,3,4,5- tetrahydro-S-phenyl-ZH-l,4benzodiazepin 2 ones. According to the present invention, the lattercompounds can be prepared directly from non-heterocyclic compounds.Thus, the present invention comprehends a process which provides afacile route for the preparation ofl,3,4,S-tetrahydro-S-phenyl-ZH-1,4-benzodiazepin-2-ones.

DETAILED DESCRIPTION OF INVENTION More particularly, the presentinvention comprehends a method for the preparation of compounds of theformula:

r N l \CHR4 R,-

R2 X I 1 R3 CH-NH-CH-CORs wherein R R R and R have the same meaning asabove, and. R is selected from the group consisting of lower alkoxy,hydroxy, aryloxy and amino.

As used herein, the term lower alkyl comprehends saturated straight andbranched chain hydrocarbon groups, for example, methyl, ethyl, propyl,isopropyl and the like. The term halogen comprehends all four halogens,i.e. iodine, bromine, fluorine and chlorine (the latter three beingpreferred). The terms lower alkyl-thio, lower alkylsulfinyl, loweralkyl-sulfonyl and lower alkoxy comprehend moieties wherein the loweralkyl part is as defined for lower alkyl above, for example, methoxy,ethoxy, methyl-thio, methyl-sulfinyl, methyl-sulfonyl and the like.Amino comprehends unsubstituted and substituted amino groups such as NHNH(lower alkyl) and N(lower alkyl) Aryloxy comprehends aromatic cyclichydro-' 'carbonoxy groups such as phenoxy and the like.

As stated above, one embodiment of this invention comprehends thepreparation of compounds of Formula I via intramolecular condensation ofcompounds of Formula II. The compounds of Formula II, depending on themeaning of R are either aminoacetic acids, amino acetates (i.e. esters),or aminoacetamides. While the intramolecular condensation can beeifected with any of these, it is preferred to effect the intramolecularcondensation utilizing compounds of Formula II which are aminoace' ticacids (i.e. R is hydroxy). In such instances the intramolecularcondensation constitutes a dehydration. The intramolecular condensationcan suitably be effected by heating a compound of Formula II in an inertorganic solvent. The dehydration embodiment (i.e. R is hydroxy)constitutes a specific exemplification of the intramolecularcondensation. This dehydration can be effected by any suitable means butpreferably is effected by heating in an inert organic solvent. Thisheating can be etfected at temperatures from about 25 C. to about 300 C.but temperatures from about C. to about 200 C. are especially preferred.Exemplary of useful organic solvents are hydrocarbons, for example,aromatic hydrocarbons such as xylene and the like, halogen containinghydrocarbons such as methylene chloride and the like, ethers such asether, diglyme, tetrahydrofuran and the like, and basic nitrogencontaining heterocycles such as pyridine, piperidine or the like.Mixtures of inert organic solvents can also be used to advantage.

Compounds of Formula II which are 2-aminobenzhydrylamino-acetic acidsare preferred starting materials for the above-described process and beprepared by a variety of methods. More particularly, they can beprepared by hydrolysis of corresponding esters or amides of the formula:

R1 aim III wherein R R R and R have the same meaning as above and R islower alkyloxy, amino or aryloxy.

The compounds of Formula II (including those of- Formula III) can beprepared via reaction of corresponding 2-aminobenz-hydrylamines with alower alkyl or aryl halo-acetate (bromo and chloroacetate are especiallypreferred), a halo-acetamide or a haloacetic vacid. This reaction can beeiiected at room temperature or at above or below room temperature.Moreover, it is suitably eifected in an inert organic solvent, forexample a hydrocarbon,

such as benzene, toluene or the like, preferably in the presence of anacid binding, i.e. acid accepting agent either inorganic or organic acidbinding agents can be used, for example, carbon-ates such as sodiumcarbonate, amines such as lower alkyl amines, for example,triethylamine, or the like.

In yet another embodiment, the compounds of Formula II can be preparedfrom benzhydrylhalides of the formula:

angen wherein R R and R have the same meaning as above; via reactionwith a glycine compound of the formula like. The so-formed benzhydrylhalide can then be isolated (advantageously in the form of its acidaddition salt, for example, as the acid addition salt formed during thehalogenation reaction) or, preferably, is further reacted by adding theglycine compound of Formula V directly to the reaction mixture in whichthe benzhydryl halide of Formula IV has been formed. A preferredembodiment of the reaction with a benzhydryl halide of Formula IVconstitutes using as the glycine compound of Formula V, a glycine ester(i.e. R is lower alkoxy or aryloxy).

The hydrolysis of the aminoacetate ester or aminoacetamide of FormulaIII to the acetic acid of Formula II is suitably effected via eitheralkaline or acid hydrolysis and can be effected at either roomtemperature or above or below room temperature. Preferably, it iseffected at above room temperature by refluxing the ester of Formula IIIin either an acidic or basic aqueous medium.

The following examples are illustrative but not limitative of theinvention. All temperatures are stated in C.

Example 1 2 amino-S-chlorobenzyhydrylamine dihydrochloride (30.6 gm.)was dissolved in water (150 ml.), and made basic with 20% sodiumhydroxide solution. Extraction of the mixture with methylene chloridegave 2-amino-5- chlorobenzhydrylamine as a pale yellow viscous oil.

Example 2 2-amino-5-chlorobenzhydrylamine (11.64 gm., 0.050 mol.),dissolved in dry benzene (100 ml.), was treated with triethylamine (7.2ml., 10.1 gm., 0.100 mol.). The reaction mixture was then stirred in anice-bath at 05, during the dropwise addition (in the course of 20-30minutes) of a solution of ethyl bromoacetate (5.52 ml., 8.35 gm., 0.050mol.) in dry benzene 20 ml.). Stirring was then continued for 16 hoursat room temperature, which was followed by refluxing the mixture on asteambath for one hour. After cooling, the reaction mixture was pouredinto water, and extracted with methylene chloride, to give a brightyellow oil. This was partitioned between dilute hydrochloric acid andether; the aqueous acid layer was made basic with sodium hydroxidesolution, and extracted with methylene chloride, to give the crudeproduct as a viscous yellow gum. Trituration with hexane, followed byseveral recrystallizations from hexane, and from ethanol, gave2-[1-(2-amino-5-chlorophenyl)-l-phenylmethylamino]acetic acid ethylester as colorless rods, M.P. 103-104 C.

Example 3 2- 1- 2-amino-5-chloropl1enyl l-phenylmethylamino] acetic acidethyl ester (1.81 gm.) was refluxed in a mixture of saturated methanolicbarium hydroxide (30 ml., circa 1 N) and water (10 ml.) for 17 hours.The resulting precipitated barium salt was filtered off after coolingthe mixture, and recrystallized from water, giving colorless needles(M.P. 206210). The barium salt was then dissolved in dimethylformamide(20 ml.), and converted to the free acid by addition of the calculatedamount of 1 N-sulfuric acid, followed by filtration to remove theprecipitated barium sulfate. Concentration of the filtrate, and dilutionwith water, gave2[l-(2-amino-5-chlorophenyl)-1-phenylrnethylamino]acetic acid as paleyellow prisms (from methanol). The melting-point was rather indefinite,circa 234242 dec.

Example 4 A suspension of 2 [1 (2-amino-5-chlorophenyl)-1-phenylmethylamino1acetic acid (1.00 gm.) in dry xylene (20 ml.) wasstirred and refluxed for six hours; some solid material remainedundissolved. The mixture was cooled and filtered, giving7-chloro-1,3,4,5-tetrahydro-5- henyl-ZH-1,4-benzodiazepin 2 one ascolorless prisms, M.P. 181-185.

Example 5 A solution of2[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino] acetic acid (1.00 gm.)in anhydrous pyridine (10 ml.) and piperidene (0.02 ml.) was refluxedfor 17 hours. The mixture was evaporated in vacuo, and the residue waspartitioned between diluted hydrochloric acid and either. The aqueousacid layer was made basic with sodium hydroxide solution, and theresulting precipitate was filtered off and recrystallized from ethanol,giving 7- chloro 1,3,4,5 tetrahydro 5 phenyl 2H 1,4 benzodiazepin-Z-oneas colorless prisms, M.P. 183185 C.

Example 6 2 amino 5 chlorobenzhydrylamine dihydrochloride (30.6 gm.,0.100 mol.), suspended in ethanol (200 ml.), was treated with anhydroussodium carbonate (21.2 gm., 0.200 mol.); the mixture was refluxed andtreated dropwise (in the course of 1 hour) with a solution of ethylbromoacetate (11.1 ml., 16.7 gm., 0.100 mol.) in ethanol (25 ml.).Stirring and refluxing were continued for 24 hours, then the mixture wasfiltered, and the combined filtrates were concentrated in vacuo. Theresulting residue was worked up in the manner described in Example 2 forthe preparation of compound2-[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino]acetic acid ethylester, giving a yellow oil. This was hydrolyzed by refluxing it with amixture of aqueous 1 N-sodium hydroxide solution ml.) and ethanol (240ml.) for 3 hours. The resulting solution was concentrated in vacuo,diluted with water, and acidified with 3 N-acetic acid (pH 5-6), to givecream-colored prisms containing2[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino]acetic acid. Theso-obtained crude product was cyclized to7-chloro-1,3,4,5-tetrahydro-S-phenyl-ZH-1,4-benzodiazepin-2-one bytreatment with refluxing xylene, as described in Example 4 givingtan-colored prisms, M.P. 182186.

Example 7 A solution of 2-amino-S-chlorobenzhydrol (23.4 grn., 0.100mol.) in ethylene dichloride (250 ml.) was stirred and treated with dryhydrogen chloride, which was bubbled through the mixture until excesswas present. Then pyridine (2 drops) and thionyl chloride (14.4 ml.,23.8 gm., 0.200 mol.) was added, and the mixture was refluxed untilevolution of sulfur dioxide virtually ceased (0.5 hour). The moxture wasthen evaporated in vacuo, with protection from atmospheric moisture. Theresidue was dissolved in methylene chloride (200 ml.) and evaporatedagain to remove excess thionyl chloride. The residue so-obtained byevaporation of the reaction mixture, was dissolved in methylene chloride(60 ml.). The solution was then stirred and cooled in an ice-bath, whilea solution of freshly distilled glycine ethyl ester (10.3 gm., 100millimoles) in methylene chloride (25 ml.), was added dropwise over thecourse of 30 minutes. The mixture was then stirred for 1 hour at roomtemperature, and poured into ice-water. The organic layer was thenevaporated giving the crude product as a brown, partly crystallineresidue. This was partitioned between ether and dilute hydrochlorideacid; the acid layer was made basic with sodium hydroxide solution, andextracted with methylene chloride, to give the almost pure product,2-[1-(2- amino-S-chlorophenyl)-1-phenylmethylamino]acetic acid ethylester, as a tan-colored crystalline residue. One recrystallization frommethyl chloride-hexane gave colorless prisms, M.P. 102-l05.

We claim:

1. A method for the preparation of compounds of the formula wherein Rand R are each selected from the group consisting of hydrogen and loweralkyl; R is selected from the group consisting of hydrogen, halogen,nitro, trifluoromethyl, lower alkyl and lower alkoxy; and R is selectedfrom the group consisting of hydrogen, halogen, trifluoromethyl, nitro,cyano, lower alkyl-thio, lower alkyl-sulfinyl, lower alkyl-sulfonyl,lower alkyl and lower alkoxy; which comprises intramolecularlycondensing a compound of the formula wherein R R R and R have the samemeaning as above, and R is selected from the group consisting ofhydroxy, lower alkoxy, aryloxy and amino.

2. A method as in claim 1 wherein R is hydroxy and the dehydration isefiected by heating in an inert organic solvent.

3. A method as in claim 2 wherein the inert organic solvent is anaromatic hydrocarbon.

4. A method as in claim 3 wherein the aromatic hydrocarbon is xylene.

5. A method as in claim 2 wherein the inert organic solvent is anitrogen containing heteroceyle.

6. A method as in claim 5 wherein the nitrogen containing heterocycle isselected from the group consisting of piperidine and pyridine.

7. A method according to claim 2 wherein the inert organic solvent is amixture of piperidine and pyridine.

8. A method for the preparation of 7-chl0ro-1,3,4,5- tetrahydro 5phenyl-ZH-1,4-benzodiazepin-2-one which comprises heating2-[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino] acetic acid.

References Cited UNITED STATES PATENTS 3,371,083 2/1968 Fryer et al260239.3

HENRY R. JILES, Primary Examiner.

R. T. BOND, Assistant Examiner.

